title: Immune-modulation and properties of absorption and blood brain barrier permeability of 1,8-naphthyridine derivatives.
abstract: Considering the high selectivity at the cannabinoid CB2 receptor of recently designed 1,8-naphthyridine derivatives and the protective role of this receptor in neurological disorders, in this study we investigated the immune-modulatory and anti-inflammatory effects of these compounds as well as their potential properties of intestinal absorption and blood-brain barrier (BBB) permeability. We used peripheral blood mononuclear cells (PBMC) known to express the CB2 receptor. We observed that test compounds, CB13, CB82 and CB91 reduced PBMC proliferation. The anti-proliferative effect of CB13 and CB91 was partially mediated by the CB2 receptor. These compounds blocked the cells cycle and CB91 reduced T cell activation. CB82 and CB91 down-regulated the expression of phosphorylated proteins like NF-κB, ERK, Akt and the enzyme Cox-2, CB91 blocked the expression of the CB2 receptor and its inhibitory effect was CB2 receptor mediated. We also investigated CB91 properties of intestinal absorption and BBB permeability in order to suggest its potential efficacy on the infiltrating auto-reactive lymphocytes at the level of the central nervous system. For this purpose, CB91 was tested in drug-permeability assays on Caco-2 cells to evaluate its oral bioavailability and on MDCKII-hMDR1 cells to estimate its BBB permeability. The results indicated that this compound possesses medium level of intestinal absorption and BBB permeability. Our data suggest that CB91, modulating the immune response by CB2 receptor mediated mechanism and showing medium level of intestinal absorption and BBB permeability, might be developed as a potential orally delivered drug and might find potential application in pathologies like multiple sclerosis.
authors.affiliation: Dipartimento di Medicina e Chirurgia, Università di Salerno Facoltà di Medicina, Baronissi Campus, Baronissi, 84081, SA, Italy, amalfitano@unisa.it.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Malfitano
authors.forename: Chiara
authors.initials: C
authors.lastname: Laezza
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saccomanni
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.forename: Clementina
authors.initials: C
authors.lastname: Manera
authors.forename: Adriano
authors.initials: A
authors.lastname: Martinelli
authors.forename: Elena
authors.initials: E
authors.lastname: Ciaglia
authors.forename: Simona
authors.initials: S
authors.lastname: Pisanti
authors.forename: Mario
authors.initials: M
authors.lastname: Vitale
authors.forename: Patrizia
authors.initials: P
authors.lastname: Gazzerro
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bifulco
mesh_terms: D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D018938:Caco-2 Cells; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D009287:Naphthyridines / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*
chemical_list: D009287:Naphthyridines; D043885:Receptor, Cannabinoid, CB2